rs35564486

Variant names:

• chr8-73981522-C-G
• rs35564486
• NM_017866.6:c.684C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-73981522-C-G
• chr8-73981522-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017866.6(TMEM70):​c.684C>G​(p.Asn228Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,790 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (6 hom.)
• Consequence: TMEM70 NM_017866.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.436
• Publications: 5 publications found

Genes affected

TMEM70 (HGNC:26050): (transmembrane protein 70) This gene likely encodes a mitochondrial membrane protein. The encoded protein may play a role in biogenesis of mitochondrial ATP synthase. Mutations in this gene have been associated with neonatal mitochondrial encephalocardiomyopathy due to ATP synthase deficiency. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

TMEM70 Gene-Disease associations (from GenCC):

• mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00697127).
• BP6: Variant 8-73981522-C-G is Benign according to our data. Variant chr8-73981522-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00504 (767/152288) while in subpopulation AFR AF = 0.0165 (687/41552). AF 95% confidence interval is 0.0155. There are 4 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017866.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	NM_017866.6	MANE Select	c.684C>G	p.Asn228Lys	missense	Exon 3 of 3	NP_060336.3
	TMEM70	NM_001040613.3		c.*374C>G		3_prime_UTR	Exon 3 of 3	NP_001035703.1
	TMEM70	NR_033334.2		n.864C>G		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM70	ENST00000312184.6	TSL:1 MANE Select	c.684C>G	p.Asn228Lys	missense	Exon 3 of 3	ENSP00000312599.5
	TMEM70	ENST00000416961.6	TSL:2	n.*441C>G		non_coding_transcript_exon	Exon 4 of 4	ENSP00000407695.2
	TMEM70	ENST00000416961.6	TSL:2	n.*441C>G		3_prime_UTR	Exon 4 of 4	ENSP00000407695.2

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 766 AN: 152170 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00169 AC: 425 AN: 251258 AF XY: 0.00142

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000637 AC: 931 AN: 1461502 Hom.: 6 Cov.: 32 AF XY: 0.000601 AC XY: 437 AN XY: 727084

African (AFR) AF: 0.0148 AC: 496 AN: 33464

American (AMR) AF: 0.00291 AC: 130 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86246

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53324

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000147 AC: 163 AN: 1111774

Other (OTH) AF: 0.00152 AC: 92 AN: 60388

GnomAD4 genome AF: 0.00504 AC: 767 AN: 152288 Hom.: 4 Cov.: 33 AF XY: 0.00533 AC XY: 397 AN XY: 74476

African (AFR) AF: 0.0165 AC: 687 AN: 41552

American (AMR) AF: 0.00320 AC: 49 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00106 Hom.: 1

Bravo AF: 0.00539

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.6
DANN	Benign	0.93
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.44
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.10
Sift	Benign	0.050	D
Sift4G	Benign	0.28	T
Polyphen		0.71	P
Vest4		0.38
MutPred		0.24		Gain of methylation at N228 (P = 0.0019)
MVP		0.31
MPC		0.49
ClinPred		0.045	T
GERP RS		0.39
Varity_R		0.098
gMVP		0.34
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35564486; hg19: chr8-74893757;